Abstract
Human papillomaviruses (HPVs) are epithelial tropic viruses that link their productive life cycles to the differentiation of infected host keratinocytes. A subset of the over 200 HPV types, referred to as high-risk, are the causative agents of most anogenital malignancies. HPVs infect cells in the basal layer, but restrict viral genome amplification, late gene expression, and capsid assembly to highly differentiated cells that are active in the cell cycle. In this study, we demonstrate that HPV proteins regulate the expression and activities of a critical cellular transcription factor, KLF4, through post-transcriptional and post-translational mechanisms. Our studies show that KLF4 regulates differentiation as well as cell cycle progression, and binds to sequences in the upstream regulatory region (URR) to regulate viral transcription in cooperation with Blimp1. KLF4 levels are increased in HPV-positive cells through a post-transcriptional mechanism involving E7-mediated suppression of cellular miR-145, as well as at the post-translational level by E6–directed inhibition of its sumoylation and phosphorylation. The alterations in KLF4 levels and functions results in activation and suppression of a subset of KLF4 target genes, including TCHHL1, VIM, ACTN1, and POT1, that is distinct from that seen in normal keratinocytes. Knockdown of KLF4 with shRNAs in cells that maintain HPV episomes blocked genome amplification and abolished late gene expression upon differentiation. While KLF4 is indispensable for the proliferation and differentiation of normal keratinocytes, it is necessary only for differentiation-associated functions of HPV-positive keratinocytes. Increases in KLF4 levels alone do not appear to be sufficient to explain the effects on proliferation and differentiation of HPV-positive cells indicating that additional modifications are important. KLF4 has also been shown to be a critical regulator of lytic Epstein Barr virus (EBV) replication underscoring the importance of this cellular transcription factor in the life cycles of multiple human cancer viruses.
Highlights
The life cycle of human papillomaviruses is dependent upon host cell replication, differentiation and cellular gene expression [1,2]
Our studies show that KLF-4, originally characterized as a pluripotency factor, binds Human papillomaviruses (HPVs)-31 promoters activating viral transcription as well as modulates host cell differentiation and cell cycle progression
KLF4 levels and activity are enhanced in HPV-positive cells by E6 and E7 mediated post-transcriptional and posttranslational mechanisms resulting in altered target gene expression and biological functions from that seen in normal keratinocytes
Summary
The life cycle of human papillomaviruses is dependent upon host cell replication, differentiation and cellular gene expression [1,2]. While one daughter cell remains in the basal layer, the other leaves the basal layer and begins to differentiate leading to productive viral replication, late gene expression, and virion assembly in suprabasal layers [1,2,4,5]. These processes are regulated by the concerted action of both viral and cellular transcription factors. These factors act either directly by binding to viral sequences in the early or late promoter regions or indirectly by modulating expression of host genes that provide critical functions for the differentiation-dependent HPV life cycle [2,3,6,7,8,9,10]
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